Pharmaceutical compositions and use of n-alkyl-1,4-dihydropyridines

ABSTRACT

PHARMACEUTICAL COMPOSITIONS EMPLOYING NOVEL 1,4-DIDIHYDROPYRIDINE DERIVATIVES ARE DESCRIBES AS WELL AS THEIR USE AS CORONARY DILATORS, HYPOTENSIVE AGENTS AND SPASMOLYTICS. A REPRESENTATIVE COMPOSITIONS IS ONE EMPLOYING 1,2,6-TRIMEMTHYL-4-(A-PYRIDYL) - 1,4 - DIHYDROPYRIDINE-3,5DICARBOXYLIC ACID DIMETHYL ESTER.

United States Patent US. Cl. 424-263 38 Claims ABSTRACT OF THEDISCLOSURE Pharmaceutical compositions employing novel1,4-dihydropyridine derivatives are described as well as their use ascoronary dilators, hypotensive agents and spasmolytics. A representativecomposition is one employing 1,2,6-trimethyl-4-(a-pyridyl) 1,4dihydropyridine-3,S- dicarboxylic acid dimethyl ester.

CROSS REFERENCE This is a continuation in part of US. Ser. No. 168,444,filed Aug. 2, 1971, now abandoned, which in turn is a division of Ser.No. 880,946, filed Nov. 28, 1969, now US. Pat. No. 3,647,807.

It is known that increasingly strong and serious disturbances of thecoronary blood supply can lead to diseases of the circulatory systemsuch as coronary insufficiency, especially angina pectoris which ispainful and often progressively grave. Conventional commercialpreparations such as nitrites or nitroglycerin while helpful have notalways provided alleviation or satisfactory treatment and although theyare widely used they have recognized limitations and disadvantages.There has therefore been numerous attempts to find better preparationswithout much success. It is the object of this invention to pronew andbetter preparations which in animal tests have shown good ability tocause coronary artery dilation at low dosage. The new compounds alsopossess spasmolytic activity and the compositions can thus be used inthe treatment of muscle spasms.

It has been found according to the present invention that1,4-dihydropyridine derivatives of the formula:

R"OOC COOR" in which R is branched or straight-chain alkyl with 1 to 3carbon atoms; or such alkyl containing a double or triple bond orsubstituted by hydroxy or alkoxy; benzyl; or substituted in the nucleusby one or more of the substituents halogen, alkyl or alkoxy;

R is hydrogen or branched or straight-chain alkyl with 1 to 3 carbonatoms;

R" is branched or straight-chain, saturated alkyl with 1 to 4 carbonatoms, or such alkyl interrupted by oxygen or substituted by hydroxyl;and

X is phenyl substituted by at least one nitro or amino group or furthersubstituted by halogen, alkyl, alkoxy or hydroxy, or 11-, 5- ory-pyridyl 3,803,314 Patented Apr. 9, 1974 Ice have therapeuticproperties which are very valuable for the beneficial treatment ofdisturbances of the coronary blood supply.

After intravenous or oral application, the new compounds or inpharmaceutical compositions, give rise to a noticeably persistentdilation of the coronary vessels and in this respect they are superiorto comparable or available commercial products. The new compounds alsohave good spasmolytic properties. They are formulated for use withconventional carriers.

The new compounds are prepared as described in US. Pat. No. 3,647,807,the disclosure of which is hereby incorporated by reference.

The most important pharmacological data are given below for arepresentative compound which is characteristic of all the compounds,1,2,6-trimethyl-4-(a-pyridyD- 1,4-dihydropyridine-3,S-dicarboxylic aciddimethyl ester.

Toxicity: DL 50, mice i.v., 79.7 mg./kg.; mice p.o., approx., 300.0mg./kg.; mice i.p., approx, 210.0 mg./ kg.

Blood pressure in rats: Strong increase of blood pressure with 10mg./kg. i.v. The initial value was not yet reached again after 20minutes. Reduced adrenaline effect.

Coronary efifect in dogs (heart catheterized):

Oxygen pressure: Narcosis: urethane-chloralose; strong increase with 50mg./kg. p.o.; return to initial value after 5 hours.

Oxygen saturation: Narcosis: phanodorm; in three experiments slightincrease with 3 mg./kg. i.v.; the initial value was not yet reachedagain after 3 /2 hours; in eight experiments slight to marked increasewith 5 mg./kg.; in four experiments the initial value was again reachedafter 3 hours, in four experiments it was not yet reached after 4 hours.

Blood pressure (dogs): Slight variations.

Frequency (dogs): No appreciable change.

The invention is illustrated by the following non-limitative examples.

EXAMPLE 1 (1) 1,2,6-trimethyl-4-(2'-nitrophenyl) 1,4dihydropyridine-3,5-dicarboxylic acid dimethylester.--2-nitrobenzaldehyde, 30 ml. of acetoacetic acid methyl ester and6 ml. of a solution of methylamine in ml. of methanol are heated underreflux for several hours, the mixture is filtered after the addition ofanimal charcoal, cooled, and 12 g. of yellow crystals of M.P. 168 to 170C. are obtained after filtering ofi with suction.

Coronary dilating effect obtained with 0.5 mgJkg. i.v., and 5 mg./kg.p.o.;

(a) Melting point of the diethyl ester 131 to 134 C.; coronary dilatingefliect obtained with 0.02 to 2 mg./kg. i.v.; good spasmolytic effect.

(b) melting point of the fi-hydroxydiethyl ester C.;

(c) l-ethyl 2,6dimethyl-4-(2'-nitrophenyl)1,4-dihyc1lLr1cgpyrcidine-3,S-dicarboxylicacid dimethyl ester, M.P.

(2) After oxidation of the2,6-dimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3,S-dicarboxylicacid diethyl ester (M.P. 124 C.) with dilute nitric acid or sodiumnitrite in glacial acetic acid to form the 2,6-dimethyl-4-(2'-nitrophenyl)-pyridine-3,S-dicarboxylic acid diethyl ester (M.P. 93to 94 C., benzene/ligroin), the oxidation product is quaternized byprolonged heating with dimethyl sulphate in a water bath, and thequaternary ammonium compound is subsequently reduced with a solution ofsodium hydrosulphite in water to form the 1,2,6-trimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine 3,5 dicarboxylic acid diethylester of M.P. 133 C.

3 EXAMPLE 2 1,2,6-trimethyl 4(3'-nitropheny1)-1,4-dihydropyridine-3,5-dicarboxylic acid diethylester.A solution of 15 g. of B-nitrobenzaldehyde, 30 g. ofa-methylamino-crotonic acid ethyl ester in 200 ml. of glacial aceticacid is heated under reflux for one hour, then poured into water andallowed to stand overnight; 25 g. of pale yellow crystals of M.P. 95 C.are obtained from methanol.

The compound obtained in the same way with 4-nitrobenzaldehyde melts at95 C.; coronary dilating effect obtained with 0.1 to 1.0 mg./ kg. i.v.

The following compounds were similarly prepared:

(a) 1,2,6-trimethyl 4(4-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methyl esterof M.P. 160 C.; coronary dilating effect with 5 mgjkg. i.v.

(b) 1,2,6-trimethyl 4(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic aciddi-(B-propoxyethyl ester) of M.P. 54 C.; coronary effect with 1 mg./kg.i.v.

(c) 1,2,6-trimethyl 4(2'-nitrophenyl)-1,4-dihydropyridine-3,S-dicarboxylic aciddi-(B-propoxyethyl ester) (oil); coronary effect with 1 to 3 mg./kg.i.v.

(d) 1-isopropyl-2,6-dimethyl 4 (2'-nitrophenyl)-1,4-dihydropyridine-3,S-dicarboxylie acid dimethyl ester of M.P. 187 C.;coronary effect with 3 mg./kg. i.v.

EXAMPLE 3 1-benzyl-2,6-dimethyl 4(3-nitro-6-chloro)-1,4-dihydropyridine-3,S-dicarboxylic acid diethylester.l 85 g. 1 mol) of 3-nitro-6-chloro-benzaldehyde are heated with270 ml. of acetoacetic acid ethyl ester and 107 g. of benzylamine in 400ml. of alcohol at boiling temperature overnight, the mixture issuction-filtered, and after prolonged standing there are obtained 246 g.of yellow crystals of M.P. 120 to 122 C.; brief coronary dilating effectobtained with 3 to mg./kg. i.v.

The l-benzyl-2,6-dimethyl 4 (4'-nitrophenyl)-1,4-dihydropyridine-3,S-dicarboxylic acid diethyl ester of M.P. 100 to 102C. is obtained in the same way (golden yellow crystals); brief coronarydilating effect obtained with 1 to 10 mg./kg. i.v.

EXAMPLE 4 l-benzyl-2,6-dimethyl 4(4-aminophenyl)-l,4-dihydropyridine-3,S-dicarboxylic acid diethylester.-After heating 120 g. ofl-benzyl-2,6-dimethyl-4-(4-nitrophenyl)-l,4dihydropyridine-3,S-dicarboxylicacid diethyl ester (M.P. 100 to 102 C.) in 400 ml. of water and 400 ml.of chlorobenzene with the addition of 400 g. of iron shavings and 6 ml.of glacial acetic acid for 8 hours, the mixture is filtered withsuction, the chlorobenzene layer is separated and the chlorobenzenedistilled off in a vacuum. From the residue there are obtained, afterrecrystallization from acetone/ether, pale-yellow crystals of M.P. 173to 175 C.

Coronary dilating effect obtained with 10 to mg./kg. i.v.

The same compound is also obtained by catalytic reduction with Raneynickel in ethanol.

EXAMPLE 5 l-(fi-hydroxyethyl)-2,6-dimethyl 4 ('y-pyridyl)-l,4-dihydropyridine-3,S-dicarboxylic acid diethyl ester.-A solution of 21.4g. of 'y-pyridinaldehyde and 12 ml. of 1- aminoethanol-2 in 52 ml. ofacetoacetic acid ethyl ester and 50 ml. of methanol is heated at boilingtemperature for several hours, filtered and cooled. After filtering offwith suction and washing with ether, white crystals g.) of M.P. 165 C.are obtained. Brief coronary dilating effect obtained with 20 mg./kg.i.v.

l-(B-hydroxyethyl)-2,6-dimethyl 4 (l3-pyridyl)-l,4-dihydropyridine-3,S-dicarboxylie acid diethyl ester, M.P. 158 C.;coronary dilating effect obtained with 10 to 20 mg./kg. i.v.

4 EXAMPLE 6 1 benzyl-2,6-dimethyl 4(u-pyridyD-lA-dihydropyridine-3,5-dicarboxylic acid diethyl ester.21.4g. of pyridine-Z-aldehyde, 52 ml. of acetoacetic ester and 22.6 g. ofbenzylamine are heated in 60 ml. of methanol at boiling temperatureovernight, the mixture is poured into water, extracted with ether andthe extract washed with a sodium chloride solution.

After distilling off the ether, there are obtained 24 g. of whitecrystals of M.P. 112 C. (benzene/ligroin). The l-benzyl-2,6-dimethyl 4(ot-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl estermelts at 180 C. (I-ICl salt).

(a) The corresponding di-tert.-butyric acid ester melts at 166 C.;coronary dilating effect obtained with 3 to S m-g./kg. i.v.;

(b) 1-benzyl-2,6-dimethyl 4('y-pyridyl)-1,4-dihydropyridine-3,S-dicarboxylic acid dimethyl ester,M.P. 182 C.;

(c) diethyl ester, M.P. 198 C.; coronary dilating effect obtained with15 mg./kg. i.v.;

(d) isopropyl ester, M.P. 146 C.; coronary dilating effect obtained with10 to 20 trig/kg. i.v.

EXAMPLE 7 l-(3',4'-dimethoxybenzyl)-2,6-dimethyl 4(B-pyridyl)-1,4-dihydropyridine-3,S-dicarboxylic acid diethylester.-After heating a solution of 10.7 g. of pyridinaldehyde, 16.7 g.of 3,4-dirnethoxy-benzylamine and 26 ml. of acetoacetic acid ethyl esterin 25 ml. of alcohol for several hours, the mixture is concentrated byevaporation in a vacuum, the residue taken up with acetone/ether, andthe reaction product precipitated as the HCl salt. After recrystallizingtwice (from acetone, then from alcohol), there are obtained yellowcrystals (30 g.) of M.P. 179 to 181 C.; coronary dilating effectobtained with 5 mglkg. i.v.

EXAMPLE 8 1,2,6 trimethyl4-(2-aminophenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethylester.-50 g. of 1,2,6- trimethyl4-(2'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid methylester are reduced in 500 ml. of methanol in the presence of 10 g. ofRaney nickel under hydrogen (in a pressure autoclave at 70 to C.), themixture is suction-filtered when the a'bsorbption of hydrogen isterminated (lb. to 2 hours), and after cooling there are obtained 24 g.of pale yellow crystals of M.P. 191 C. Brief coronary dilating effectobtained with 5 mg./kg. i.v.

The 1,2,6trimethyl-4-(3-aminophenyl)-1,4-dihydropyridine-3,S-dicarboxylic aciddiethyl ester has a M.P. of 134 to 136 C.; coronary dilating effectobtained with 5 to 10 mg./kg. i.v.

EXAMPLE 9 1,2,6 trimethyl-4-(3-nitro-4'-hydroxyphenyl)-1,4-dihydropyridine 3,5-dicarboxylic aciddiethyl ester.After heating 8.5 g. of 3-nitro-4-l1ydroxy-benzaldehyde,15 ml. of acetoacetic acid ethyl ester and 6 ml. of a 30% to 40% aqueousmethylamine solution in 50 ml. of alcohol for several hours,concentrating the mixture by evaporation and adding ether, there areobtained 7 g. of yellow crystals of M.P. 142 C.; coronary dilatingeffect obtained with 3 mg./kg. i.v.

In the same way there were obtained:

(a) 1,2,6 trimethyl 4-(2'-nitro-5'-hydroxyphenyl)-1,4-dihydropyridine-3,S-dicarboxylic acid dimethyl ester of M.P. 237 C.;coronary dilating effect obtained with 3 to 10 trig/kg. i.v.

(b) 1,2,6 trimethyl 4-(2-nitro-S-hydroxyphenyl)-1,4-

dihydropyridine-,3,S-dicarboxylic acid diethyl ester of M.P. 197 C.;coronary dilating effect obtained with. 10) mg./kg. i.v.

(c) 1,2,6 trimethyl 4 (4'-nitro-3-hydroxyphenyl)-1,4dihydropyridine-3,S-dicarboxylic acid dimethyl ester of M.P. 187 C.;coronary dilating effect obtained with mg./kg. i.v.

(d) 1,2,6 trimethyl 4-(4'-nitro-3-hydroxyphenyl)-1,4-

dihydropyridine-3,S-dicarboxylic acid diethyl ester of M.P. 151 C.;coronary dilating effect obtained with 10 mg./kg. i.v.

EXAMPLE 10 1,2,6 trimethyl 4 (a-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester.-After heating a solution of ml. ofpyridine-2-aldehyde, 50 ml. of acetoacetic acid methyl ester and 30 ml.of a 30% to 40% aqueous solution of methylamine in 100 ml. of methanolunder reflux for 2 to 3 hours, the mixture is filtered with suctionthrough animal charcoal and concentrated to half its volume. After theaddition of ether and cooling, 5 g. of pale yellow crystals areobtained; white crystals of M.P. 160 to 162 C. from methanol.

The following compounds were also prepared:

(a) 1,2,6 trimethyl 4-(oc-pyridyl)-1,4-dihydropyridine- 3,5-dicarboxylicacid diethyl ester of M.P. 106 C.; coronary dilating effect obtainedwith 1 to 2 mg./kg. i.v.

(1:) 1,2,6 trimethyl -4-(B-pyridyl)-l,4-dihydropyridine-3,5-dicarboxy1ic acid dimethyl ester of M.P. 190 C. (HCl salt); briefcoronary dilating effect obtained with 3 to 5 mg./kg. i.v.

(c) N isopropyl2,6-dimethyl-4-(a-pyridyl)-1,4-dihydropyridine-3,S-dicarboxylic aciddimethyl ester of M.P. 131 C.

(d) N allyl2,6-dimethyl-4-(u-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic aciddimethyl ester of M.P. 106 C.; brief coronary dilating eifect obtainedwith 2 mg./ kg. i.v.

(e) 1,2,6 trimethyl 4-(a-pyridyl)-l,4-dihydropyridine- 3,5-dicarboxylicacid diisopropyl ester of M.P. 115 C.; coronary dilating eflect obtainedwith 2 mg./kg. i.v.

(f) 1,2,6 trimethyl 4-(a-pyridyl)-1,4-dihydropyridine- 3,5-dicarboxylicacid-di-(B-methoxyethyl-ester) of M.P. 108 C.; coronary dilating eflectobtained with 3 to 5 mg./kg. i.v.

(g) 1,2,6 trimethyl 4-(B-pyridyl)-1,4-dihydropyridine- 3,5-dicarboxylicacid-di-(B-propoxyethyl-ester) of M.P. 58 C.; coronary dilating effectobtained with 1 to 2 mg./ kg. i.v.

(h) 1,2,6 trimethyl 4-(a-pyridyl)-l,4-dihydropyridine- 3,5-dicarboxylicacid-di-(fi propoxyethyl-ester) of M.P. 88 C.; coronary dilating effectobtained with 2 to 3 mg./kg. i.v.

EXAMPLE ll Pharmaceutical compositions are prepared so as to contain amajor or minor amount, e.g. from 95 to 0.5%, of at least onedihydropyridine as herein defined in combination with a pharmaceuticalcarrier, the carrier comprising one or more solid, semisolid or liquiddiluent, filler and formulation adjuvant which is nontoxic, inert andpharmaceutically acceptable. Such pharmaceutical compositions arepreferably in dosage unit form; i.e. physically discrete unitscontaining a predetermined amount of the drug corresponding to afraction or multiple of the dose which is calculated to produce thedesired therapeutic response. The dosage units can contain one, two,three, four or more single doses or, alternatively, one-half, third orfourth of a single dose. A single dose preferably contains an amountsufiicient to produce the desired therapeutic effect upon administrationat one application of one or more dosage units according to apredetermined dosage regimen, usually a whole, half, third or quarter ofthe daily dosage administered once, twice, three or four times a day.Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefullyadjusted, utilizing sound professional judgment and considering the age,weight and condition of the recipient, the route of administration andthe nature and gravity of the illness, generally the daily dose will befrom about 0.01 to about 10 mg./kg. In some instances a sufiicienttherapeutic effect can be obtained at a lower dose while in others, alarger dose will be required.

Oral administration can be effected utilizing solid and liquid dosageunit forms such as powders, tablets, dragees, capsules, granulates,suspensions, solutions and the like.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate as for example starch, lactose, sucrose, glucose ormannitol. Sweetening, flavoring, preservative, dispersing and coloringagents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

lIablets are formulated for example by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally with a binder such as carboxymethyl cellulose, analginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas parafiin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acacia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alernative togranulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Themedicaments can also be combined with free flowing inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing coat of shellac, a coating of sugar or polymeric material and apOlish coating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous sucrose solution while elixirsare prepared through the use of a nontoxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a nontoxicvehicle. Solubilizers and emulsifiers such as ethoxylated isostearylalcohols and polyoxyethylene sorbitol esters, preservatives, flavoradditives such as peppermint oil or saccharin, and the like can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

Parenteral administration can be effected utilizing liquid dosage unitforms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anontoxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be pro vided for mixing prior to administration.Nontoxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservatives and emulsifiers, can also be added.

Rectal administration can be effected utilizing suppositories in whichthe compound is admixed with low melting water soluble or insolublesolids such as polyethylene glycol, cocoa butter, higher esters as forexample myristyl palmitate, or mixtures thereof.

The foregoing examples of pharmaceutical compositions can utilize eachof the individual compounds recited in Examples 1-10.

What is claimed is:

1. A pharmaceutical composition for use in the dilation of coronaryarteries and the treatment of spasms comprising an effective amount of acompound of the formula:

R"OOC l l-COOH."

in which {R is a branched or straight-chain alkyl with 1 to 3 carbonatoms, or such alkyl having a double or triple bond or substituted byhydroxy or alkoxy, benzyl, or benzyl substituted in the nucleus by oneor more of the substituents halogen, alkyl, alkoxy; R is hydrogen orbranched or straightchain alkyl with l to 3 carbon atoms;

R" is branched or straight-chain, saturated alltyl with '1 to 4 carbonatoms, or such alkyl interrupted by oxygen or substituted by hydroxyl;and

X is phenyl substituted by at least one nitro or amino group or furthersubstituted by halogen, alkyl, alkoxy or hydroxy, or a-, 5- or'y-pyridyl, and a pharmaceutical carrier.

2. A composition according to claim 1 wherein said compound is1,2,6-trimethyl-4(2'-nitrophenyl)-l,4-dihydropyridine 3,5-dicarboxylicacid diethyl ester.

3. A composition according to claim 1 wherein said compound is1,2,6-trimethyl-4(3'-nitrophenyl)-l1,4dihydropyridine-2,5-dicarboxylicacid diethyl ester.

4. A composition according to claim 1 wherein said compound is1,2,6-trimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine 3,5 dicarboxylicacid di-(fi-hydroxyethyl) ester.

5. A composition according to claim 1 wherein said compound is1-ethyl-2,'6-dimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3,S-dicarboxylic acid dimethyl ester.

6. A composition according to claim 1 wherein said compound is1,2,6-trimethyl-4-(3-nit.rophenyl)-1,4dihy dropyridine-3,S-dicarboxylicacid diethyl ester.

7. A composition according to claim 1 wherein said compound is 1,2,6trimethyl 4 (4' nitrophenyl)-l,4- dihydropyridine-3,S-dicarboxylic acidmethyl ester.

8. A composition according to claim 1 wherein said compound is 1,2,6trimethyl 4 (3' nitrophenyl)-1,4-

dihydropyridine-3,5,-dicarboxylic acid di-(fl-propoxyethyl ester).

9. A composition according to claim 1 wherein said compound is 1,2,6trimethyl 4 (2' nitrophenyl)-1,4- dihydropyridine-3,S-dicarboxylic aciddi-(fi-propoxyethyl ester).

10. A composition according to claim 1 wherein said compound is 1isopropyl 2,6 dimethyl 4 (2'-nitrophenyl)-1,4-dihydropyridine 3,5dicarboxylic: acid dimethyl ester.

- 11. A composition according to claim 1 wherein said compound is 1benzyl 2,6 dimethyl 4 (3'-nitro-6- 8 chloro) 1,4 dihydropyridine 3,5dicarboxylic acid diethyl ester.

12. A composition according to claim 1 wherein said compound is 1 benzyl2,6 dimethyl 4 (4 nitrophenyl) 1,4 dihydropyridine 3,5 dicarboxylic aciddiethyl ester.

13. A composition according to claim 1 wherein said compound is 1 benzyl2,6 dimethyl 4 -(4 aminophenyl) 1,4 dihydropyridine 3,5 dicarboxylicacid diethyl ester.

14. A composition according to claim 1 wherein said compound is l (Bhydroxyethyl) 2,6 dimethy1-4-(-ypyridyl) 1,4 dihydropyridine 3,5dicarboxylic acid diethyl ester.

15. A composition according to claim 1 wherein said compound is 1 ((3hydroxyethyl) 2,6 dimethyl-4- (fl pyridyl) 1,4dihydropyridine-3,S-dicarboxylic acid diethyl ester.

16. A composition according to claim 1 wherein said compound is 1 benzyl2,6 dimethyl 4 (a-pyridyD- 1,4 dihydropyridine 3,5 dicarboxylic aciddiethyl ester.

17. A composition according to claim 1 wherein said compound is l benzyl2,6 dimethyl 4 (a-pyridyl)- 1,4 dihydropyridine 3,5 dicarboxylic aciddi-tert.- butyric acid ester.

18. A composition according to claim 1 wherein said compound is 1 benzyl2,6 dimethyl 4 ('y-pyridyD- 1,4 dihydropyridine 3,5 dicarboxylic aciddimethyl ester.

19. A composition according to claim 1 wherein said compound is 1 benzyl2,6 dimethyl 4 y-pyridyl) 1,4 dihydropyridine 3,5 dicarboxylic aciddiethyl ester.

20. A composition according to claim 1 wherein said compound is 1 benzyl2,6 dimethyl 4 ('y-pyridyD- 1,4-dihydropyridine 3,5 dicarboxylic acidisopropyl ester.

21. A composition according to claim 1 wherein said compound is 1 (3',4'dimethoxybenzyl)-2,6-dimethyl- 4 (t3 pyridyl) 1,4dihydropyridine-3,S-dicarboxylic acid diethyl ester.

22. A composition according to claim 1 wherein said compound is 1,2,6trimethyl 4 (2' aminophenyl)-1,4 dihydropyridine-3,S-dicarboxylic aciddimethyl ester.

23. A composition according to claim 1 wherein said compound is 1,2,6trimethyl 4 (3' aminopheny1)- 1,4 dihydropyridine 3,5 dicarboxylic aciddiethyl ester.

24. A composition according to claim 1 wherein said compound is 1,2,6trimethyl 4 (3' nitro4'-hydroxyphenyl) 1,4 dihydropyridine 3,5dicarboxylic acid diethyl ester.

25. A composition according to claim 1 wherein said compound is 1,2,6trimethyl 2 (2' nitro-5'-hydroxyphenyl) 1,4 dihydropyridine 3,5dicarboxylic acid dimethyl ester.

26. A composition according to claim 1 wherein said compound is 1,2,6trimethyl 4 (2' nitro-S'-hydroxyphenyl) 1,4 dihydropyridine 3,5dicarboxylic acid diethyl ester.

27. A composition according to claim 1 wherein said compound is 1,2,6trimethyl 4 (4 nitro 3'-hydroxyphenyl) 1,4 dihydropyridine 3,5dicarboxylic acid dimethyl ester.

28. A composition according to claim 1 wherein said compound is 1,2,6trimethyl 4 (4' nitro-3'-hydroxy phenyl) 1,4 dihydropyridine 3,5dicarboxylic acid diethyl ester.

29. A composition according to claim 1 wherein said compound is 1,2,6trimethyl 4 (oz pyridyl)-1,4-dihydropyridine 3,5 dicarboxylic aciddimethyl ester.

30. A composition according to claim 1 wherein said compound is 1,2,6trimethyl 4 (a pyridyl)-1,4- dihydropyridine 3,5 dicarboxylic aciddiethyl ester.

31. A composition according to claim 1 wherein said compound is 1,2,6trimethyl 4 -(B pyridyl) 1,4- dihydropyridine 3,5 dicarboxylic aciddimethyl ester.

32. A composition according to claim 1 wherein said compounds Nisopropyl 2,6 dimethyl 4-(a-pyridyl)- 1,4 dihydropyridine 3,5dicarboxylic acid dimethyl ester.

33. A composition according to claim 1 wherein said compound is N allyl2,6 dimethyl 4 (a-pyridyD- 1,4 dihydropyridine 3,5 dicarboxylic aciddimethyl ester.

34. A composition according to claim 1 wherein said compound is 1,2,6trimethyl 4 (a-pyridyl)-1,4-dihydropyridine 3,5 dicarboxylic aciddiisopropyl ester.

35. A composition according to claim 1 wherein said 1 compound is 1,2,6trimethyl 4 (a pyridyl)-1,4-dihydropyridine 3,5 dicarboxylic aciddi-(fl-methoxyethyl-ester).

36. A composition according to claim 1 wherein said compound is 1,2,6trimethyl 4 (p-pyridyl)-1,4-dihydropyridine 3,5 dicarboxylic aciddi-(B-propoxyethyl-ester).

37. A composition according to claim 1 wherein said compound is 1,2,6trimethyl 4 (a pyridyl)-1,4- dihydropyridine 3,5 dicarboxylic aciddi-(p-propoxyethyl-ester).

38. The method of effecting dilation of the coronary arteries whichcomprises administering to an animal in need thereof an effective amountof a compound of the formula:

ROOC I l coon" I I R N/ R It in which R is a branched or straight-chainalkyl with 1 to 3 carbon atoms, or such alkyl having a double or triplebond or substituted by hydroxy or alkoxy, benzyl, or benzyl substitutedin the nucleus by one or more of the substituents halogen, alkyl,alkoxy;

R is hydrogen or branched or straight-chain alkyl with 1 to 3 carbonatoms;

R" is branched or straight-chain, saturated alkyl with with 1 to 4carbon atoms, or such alkyl interrupted by oxygen or substituted byhydroxyl; and

X is phenyl substituted by at least one nitro or amino group or furthersubstituted by halogen, alkyl, alkoxy or hydroxy, or w, flor 'y-pyridyl,

and a pharmaceutical carrier.

References Cited UNITED STATES PATENTS 3,485,847 12/1969 Bossert et a1260295.5 3,488,359 11/1970 Bossert et a1. 26029'5.5 3,441,648 4/1969Loev et a1. 260-2955 3,511,847 5/ 1970 Loev et a1. 260-2955 STANLEY I.FRIEDMAN, Primary Examiner

